Study of Adoptive Transfer of Invariant Natural Killer T Cells Combined With TAE/TACE to Treat Unresectable Hepatocellular Carcinoma (HCC): Phase II Clinical Trial

Hepatocellular carcinoma (HCC) is a common disease with high mortality. More than 80% patients receive a diagnosis when their tumors are too advanced for curative approaches and have a dismal prognosis. invariant Natural Killer T (iNKT) cell exhibit antitumor activity against malignant tumors through producing high levels of cytokines. iNKT cells are abundant in the liver, but their function is defective in liver cancer. After expansion and restored function in vitro, iNKT cells can home to liver, then they play key antitumor function. We have finished a phase I study of adoptive transfer of autologous iNKT cells for treating patients with unresectable HCC. Safety and feasibility of iNKT infusion was proved. The purpose of this study was to verify the effectiveness of iNKT cell infusion in patients with unresectable HCC who had previously failed transcatheter arterial embolization (TAE) / transcatheter arterial chemoembolization (TACE).

开始日期2018-03-01

申办/合作机构

首都医科大学附属北京佑安医院

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2024-09-01·Inflammation Research

Alpha-galactosylceramide pre-treatment attenuates clinical symptoms of LPS-induced acute neuroinflammation by converting pathogenic iNKT cells to anti-inflammatory iNKT10 cells in the brain

Article

作者: Park, Yun Hoo ; Lee, Sung Won ; Park, Hyun Jung ; Kim, Tae-Cheol ; Hong, Seokmann ; Van Kaer, Luc

BACKGROUNDInvariant natural killer T (iNKT) cells play protective or pathogenic roles in a variety of immune and inflammatory diseases. However, whether iNKT cells contribute to the progression of acute neuroinflammation remains unclear. Thus, we addressed this question with a mouse model of lipopolysaccharide (LPS)-induced acute neuroinflammation.METHODSFor induction of acute neuroinflammation, wild-type (WT) C57BL/6 (B6) mice were injected intraperitoneally (i.p.) with LPS for either three or five consecutive days, and then these mice were analyzed for brain-infiltrating leukocytes or mouse behaviors, respectively. To examine the role of iNKT cell activation in LPS-induced neuroinflammation, mice were injected i.p. with the iNKT cell agonist α-galactosylceramide (α-GalCer) seven days prior to LPS treatment. Immune cells infiltrated into the brain during LPS-induced neuroinflammation were determined by flow cytometry. In addition, LPS-induced clinical behavior symptoms such as depressive-like behavior and memory impairment in mice were evaluated by the open field and Y-maze tests, respectively.RESULTSWe found that iNKT cell-deficient Jα18 mutant mice display delayed disease progression and decreased leukocyte infiltration into the brain compared with WT mice, indicating that iNKT cells contribute to the pathogenesis of LPS-induced neuroinflammation. Since it has been reported that pre-treatment with α-GalCer, an iNKT cell agonist, can convert iNKT cells towards anti-inflammatory phenotypes, we next explored whether pre-activation of iNKT cells with α-GalCer can regulate LPS-induced neuroinflammation. Strikingly, we found that α-GalCer pre-treatment significantly delays the onset of clinical symptoms, including depression-like behavior and memory impairment, while decreasing brain infiltration of pro-inflammatory natural killer cells and neutrophils, in this model of LPS-induced neuroinflammation. Such anti-inflammatory effects of α-GalCer pre-treatment closely correlated with iNKT cell polarization towards IL4- and IL10-producing phenotypes. Furthermore, α-GalCer pre-treatment restored the expression of suppressive markers on brain regulatory T cells during LPS-induced neuroinflammation.CONCLUSIONOur findings provide strong evidence that α-GalCer-induced pre-activation of iNKT cells expands iNKT10 cells, mitigating depressive-like behaviors and brain infiltration of inflammatory immune cells induced by LPS-induced acute neuroinflammation. Thus, we suggest the prophylactic potential of iNKT cells and α-GalCer against acute neuroinflammation.

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2023-10-10

·PRNewswire

The SparX Group Enters into a Collaboration with Arovella Therapeutics for the Development of CLDN18.2-CAR-iNKT Cell Therapy

CHICAGO, Oct. 10, 2023 /PRNewswire/ -- Signifying a monumental step forward in the domain of powered antibody therapies, the SparX Group is thrilled to unveil its strategic alliance with Arovella Therapeutics Ltd (ASX: ALA). This collaboration emphasizes the utilization of SPX-101, an innovative monoclonal antibody (mAb) that targets the Claudin 18.2 (CLDN18.2) tumor specific antigen, as an exciting component in Arovella's CLDN18.2-CAR-iNKT cells as a leading off-the-shelf CAR-iNKT cell therapy. Dr. Gui-Dong Zhu, CEO of the SparX Group, elucidated on the significance of this collaboration: "Our partnership with Arovella represents a transformative phase in advancing mAb-based therapies. Invariant Natural Killer T (iNKT) cells, distinguished by their recognition of lipid antigens via the CD1d molecule, have emerged as potent therapeutic vectors. Arovella's cutting-edge CAR-iNKT platform, encapsulating advanced techniques for in-vitro expansion and post-infusion persistence of iNKT cells, underscores their leadership in this domain. We profoundly acknowledge CLDN 18.2-iNKT cell therapy as a groundbreaking paradigm in oncological therapeutics." Echoing the enthusiasm, Dr. Michael Baker, CEO of Arovella, remarked, "Licensing the CLDN18.2 mAb sequence from SparX represents a seminal phase in our therapeutic trajectory. SparX's sophisticated work, spotlighting the unparalleled attributes of their CLDN18.2 monoclonal antibody, coupled with its safety and specificity, accentuates the global attention this molecular target is garnering. We're uniquely positioned as the only global entity developing a CAR-iNKT cell therapy aimed at CLDN18.2. The synergistic combination of iNKT cells with the CLDN18.2 CAR paves an exciting avenue to develop novel cancer therapeutics." CLDN18.2 manifests predominantly in gastric cancers (GC), gastroesophageal junction cancers (GEJC), pancreatic cancers (PC), and a spectrum of other solid tumors. Both GC and GEJC represent formidable clinical challenges, registering over a million new cases annually worldwide and culminating in 770,000 fatalities. This places them as the fourth leading cause of cancer-related deaths globally. Spearheaded by SparX, SPX-101 embodies a pinnacle of molecular engineering, stemming from SparX's sophisticated SAILINGTM discovery platform. This mAb is designed for optimized therapeutic efficacy, offering the potential to be recognized as a best-in-class molecular entity targeting claudin 18.2. Expounding on the cellular dynamics, Invariant Natural Killer T (iNKT) cells are a specialized T cell subset known for recognizing lipid antigens via the CD1d molecule. These cells possess inherent attributes like tissue infiltration capabilities, counteracting tumor-promoting cells such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), and orchestrating a robust immune response by recruiting auxiliary immune cells against tumor sites. The pathological architecture of tumor development often exposes the CLDN18.2, rendering it accessible to novel treatments such as CAR-iNKT cell therapies. Preliminary clinical findings indicate that iNKT cell therapies might proffer a superior safety profile relative to alternative T cell therapies, notably displaying a reduced propensity for cytokine release syndrome, a prevalent and potential adverse reaction observed in certain cell therapies. About SparX Biopharmaceutical: A research-driven, development-stage biopharmaceutical trailblazer, SparX Biopharmaceutical Corp. has a mission of "amplifying human immunity with groundbreaking antibody therapies." Through the utilization of big data analytics, including machine learning, SparX decrypts potential interactions within the vast complexity of biological information. With meticulous pharmacological analyses, backed by in vitro and in vivo evaluations using advanced mouse models, SparX is on a relentless quest to develop unparalleled or superior therapeutics. SparX's robust target discovery platform, combined with the multifaceted SAILING™ antibody optimization system and groundbreaking bi-ADC technology, is poised to redefine the success metrics of empowered antibody drug development. Equipped with in-house cGMP facilities, SparX is on track to become a self-sustaining, fully integrated biopharmaceutical entity. SOURCE SparX Group

细胞疗法免疫疗法抗体药物偶联物

2022-11-10

·Endpoints

In waning Covid market, MiNK unveils data on natural killer T cell therapy for ARDS, pending contract with DARPA

In an SITC poster, Agenus’ spinout MiNK Therapeutics dropped the results of a Phase I/II study of its lead candidate, made from rare immune cells known as invariant natural killer T cells, or iNKT cells for short, for treating acute respiratory distress syndrome (ARDS), a serious complication of Covid. MiNK was and still is developing the iNKT therapy, dubbed agenT-797, for treating cancer, but like others, it pivoted during the pandemic and started a small 20-person study in ARDS patients who were intubated or at high risk of being intubated. In the trial, patients who got MiNK’s therapy had a 70% chance of survival compared to 10% in a case control group of 20 patients at 30 days. In a more severe subgroup, three of four patients who were on ECMO, essentially an artificial lung machine, and got agenT-797 on top of that survived through 90 days. Patients were dosed through October 2020 to February of this year, spanning multiple strains of Covid. MiNK CEO Jennifer Buell emphasized that MiNK is still very much a cancer company, but it generated data around ARDS because of the pandemic. “We hadn’t launched the company to study the cells in this setting, but we knew historically that the cells were active in SARS-CoV-1, MERS,” Buell said. However, the data come at a time at which companies are seeing their Covid-related sales fall. This past quarter, Pfizer saw its first revenue dip since its vaccine was authorized in 2020. And Moderna also cut its sales forecast during its Q3 report. Moving forward, MiNK will continue to focus on the cancer applications of its iNKT cell therapy, but it will push the ARDS indication forward in a “non-dilutive way” through a pending DARPA contract, Buell said. Buell noted that they are still in negotiations, but added that they could also look at other non-cancer indications. “We think that the benefit that we’ve observed in viral ARDS may be applicable to other lung diseases, fibrosis — there are a few other idiopathic lung diseases,” she said. MiNK also presented very early cancer data with a median follow-up of 4 months. In patients with solid tumors who were treated with two to 11 lines of previous therapy, 5 had stable disease while 9 had progressive disease after receiving the iNKT cell therapy. Some got agenT-797 alone while others got it in combination with Keytruda or Opdivo. In eight evaluable patients with multiple myeloma, two had stable disease while the rest had progressive disease. MiNK went public in October of last year under $INKT , but while it started out at around $12 a share, it’s now trading at around $2.50 — down around 80% all-time — amid the wider market downturn.

疫苗细胞疗法

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